Drug Addiction  A (Forgotten) Memory?

by: Frank Adam
Date: November 2005

Click. Click. Click. The rat's paw repeatedly taps the lever in front of it. Click. Click. Click. Each lever strike produces a surge of pleasure in the animal's brain; every "click" is a hit of cocaine in this animal-style drug addiction.

But why subject a rat to a self-administered intracranial supply of cocaine? What does a "high" rat have to tell science? In the above case, the rat is providing invaluable data concerning an enormous societal crisis: that of drug addiction.

Costing the nation more than $143 billion annually, according to the National Office of Drug Control, substance abuse truly ranks as one of the most expensive dilemmas of modern America.

Figure 1. Powder cocaine. Rats addicted to powder cocaine can overcome their addiction by interrupting the memories associating the drug with environmental cues. But could such a therapy work on humans? Images Courtesy of US Drug Enforcement Administration.

Despite the deadly grasp a drug can have upon a person, many drug abusers endeavor to break the cycle of addiction and return to a normal life. This is not an easy process, though. Many drugs cause physiological changes to occur in the brain that result in permanent damage to the user. Furthermore, the potential for relapse is unfortunately very high; exposure to settings the user associates with the drug is particularly hazardous to relapses. A study in Los Angeles found that 22% of women and 32% of men recovering from drug abuse are likely to relapse within six months.

But hope exists for those trying to reclaim their lives. Neuroscientists are continually expanding our knowledge of the inner workings of the brain and how drugs hijack the normal functions of the mind. Using animal models, researchers have peered deep into the cellular and molecular mechanisms underlying drug addiction. Additionally, researchers are spotlighting various functions of the brain, such as memory and emotion, as targets for addiction therapy.

Perhaps most exciting is the latest research concerning methods to combat relapse. John Marshall of the University of California at Irvine and Jonathon Lee of Cambridge University have both found a way to block the reinforcing memories that formerly drug-addicted rats associate with their drug. Ultimately, these researchers are working within rat neurons to erase memories of drug abuse so that reformed rat-addicts can return to a (rat) normal lifestyle. But first, how are memories normally stored in the brain; and, how might someone modulate this process?

Models of Memory

There are some truly nutty structures in the brain. For instance, most people don't know they have a seahorse swimming around inside their head. That's right; Giulio Cesare Aranzi, an ancient anatomist, saw a brain structure that he called the hippocampus, or seahorse in Greek, due to its remarkable resemblance to the animal. Another example is the amygdala (sounds like a Star Wars character), a small group of cells near the front of the hippocampus that share its circuitry. This little aquatic creature and its sidekick are part of a larger grouping known as the Limbic System, a central memory and emotion processor in the brain.

Learning and memory may be one of the most interesting and complex topics in neuroscience. How can a group of cells recall facts, faces, names, places, and skills  all accessible on demand? This fundamental question in neuroscience has no simple answer. However, neuroscientists and psychologists have constructed many theories and models to describe the forms and functions of memory.

Figure 2. The various forms of memory. Image Courtesy: J.P. Card of University of Pittsburgh.

What one usually considers memory  such as active recall of facts  is only one small subset of what neuroscientists and psychologists broadly consider memory. A variety of different cognitive functions, some unconscious, constitute a recall of stored information and are thus considered "memory."

For instance, when you hop on your bike to cruise down the road, you're utilizing a form of memory that codes for actions. You don't have to think about it  your body remembers how. Another example of memory, though a simplified form, is that of habituation; here an animal experiences repetitive exposure to something in its environment, perhaps a noise or a flash of light, which eventually leads the animal to ignore this cue.

However, the form of memory affecting drug addiction is conditioning. This form of learning and memory, first demonstrated by Ivan Pavlov, is ubiquitous within the animal kingdom and often guides unconscious actions.

Experiments have shown that when memories are first acquired they must undergo an active process in the brain known as consolidation. Here, the brain synthesizes new proteins and makes new neural connections to cement the memory. When memory is later retrieved, it enters a moldable state that leaves it open to change. To make sure the memory is properly stored again, the brain must reconsolidate the memory. This process of reconsolidation has led both Marshall and Lee to wonder: is it possible to completely disrupt the proper storage of a memory by interrupting reconsolidation?

The Forgotten Memories

Marshall and Lee are using rats to find an answer. In their experiments, they inject the psychoactive drug cocaine into a rat's veins or brain while giving it an environmental cue that the rat will associate with the pleasure of the drug. For example, Marshall placed a rat in a chamber with one area demarcated by a distinctive checkered pattern. Initially, the animal showed no preference for any particular area of the chamber; however, this changed. Marshall gave the rat drug injections only in the checkered area, and soon the animal associated the checkered patterns with the pleasure of the drug and would voluntarily move to this area of the cage even without drug injections.

Once the rats have associated the checkered room with the drugs, the only way to break the association is to disrupt the memory's reconsolidation.

Lee attempted this by disrupting the protein synthesis processes that occur during memory reconsolidation. In his experiments, Lee injected an addicted rat's amygdala with a substance that blocks an important molecule in reconsolidation. His rats, which previously associated light with cocaine, ceased associating the two. But it's not that the rat simply "forgot:"

"The memory that linked the light with cocaine was unable to direct or influence behavior following the disruption of its reconsolidation," says Lee.

Similarly, Marshall has disrupted proteins, called ERKs, involved in drug-memory reconsolidation by injecting substances into the nucleus acumbens, a hotspot for addiction in the pleasure circuits of the brain. Again, it was as though the animals completely forgot their preference for a particular cage location - and the forgetfulness lasted for the whole 2 weeks that researchers observed them.

"Memories responsible for relapse in drug addicts may be similarly disrupted by a therapeutic agent targeting ERK or related proteins," says Marshall.

"We need to investigate whether [reconsolidation disruption] is applicable to old and strong drug memories," says Lee. Also, he hopes to move in the direction of a human therapy for drug addiction: "We need to identify a suitable drug treatment that can be used to disrupt memory reconsolidation when administered systemically.without side-effects."

Though these exciting results will aid addiction recovery, the prospect of altering one's memory with a simple pill is frightening. The power to change the past as we know it is a burdensome responsibility that scientists do not take lightly. Both legal and ethical issues arise when one's memory can permanently be changed.

The President's Council on Bioethics, in an October 2002 report, made a succinct summary of the issue at hand, closing with a potent prescript: ".the development of powers over the workings of memory for one purpose - perhaps laudable or justifiable - may open the door to other kinds of modifications that are more ambiguous, dangerous, or dehumanizing.[these powers] only challenge us to proceed wisely and with eyes open, so that we avoid the worst outcomes of our new bio-technical powers and realize the best."

Still, the future is looking brighter, both for recovering addicts and society as a whole as treatments for drug addiction are on the horizon in neuroscience. Through drug-associated memory disruption, addicts attempting to return to a normal life may find this road a little easier to tread. And the benefit to the nation of fewer drug users, less drug traffic, and a reduction in drug-related accidents will be truly invaluable. However, consider the true warrior in this battle, the one who deserves so much credit, for without the laboratory rat, none of this fascinating work would have been possible: cheers to the rats!

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